The adrenal hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) have been negatively correlated with insulin levels, cardiovascular morbidity, cancer, obesity and diabetes. However, the mechanism of the association is unclear. Insulin acts as a physiological regulator of DHEA/DHEA-S metabolism; hyperinsulinemia decreases serum DHEA-S in normal subjects and in women with polycystic ovary syndrome (PCOS), while increasing androstenedione (D4-A) and testosterone levels conversely. The divergent correlations of circulating DHEA-S and testosterone/adrostenedione combined with the animal data of diet effects of DHEA suggest that DHEA-S and testosterone may therefore exert opposing effects on insulin secretion and action.